Oropharyngeal Cancer Imaging; Anatomy and Pathways of Spread in Staging and Treatment Planning

Transcription

1 Oropharyngeal Cancer Imaging; Anatomy and Pathways of Spread in Staging and Treatment Planning Poster No.: R-0171 Congress: 2014 CSM Type: Scientific Exhibit Authors: J. Cui, S. Bhuta ; GOLD COAST/AU, SOUTHPORT/AU Keywords: Endoscopy, Contrast agent-other, MR, CT, Head and neck, Metastases DOI: /ranzcr2014/R Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply RANZCR/AIR/ACPSEM's endorsement, sponsorship or recommendation of the third party, information, product or service. RANZCR/AIR/ ACPSEM is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold RANZCR/AIR/ACPSEM harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies,.ppt slideshows,.doc documents and any other multimedia files are not available in the pdf version of presentations. Page 1 of 40

2 Aim Learning Objectives: Understand the anatomy of the oropharynx and its relationship to surrounding structures Assess the Lymph nodal stations/levels and drainage patterns in oropharyngeal primaries Identify subsites of the oropharynx and common locations of primary SCC Common patterns of spread of primary tumors and how they influence the TNM staging Introduction: Oropharynx is the part of the pharynx which lies between the soft palate and the upper edge of the epiglottis at the level of the hyoid bone. (Fig. 1 on page 3) It contains extensive lymphatic drainage and also structures that are in close proximity to one another. This can add difficulty to the diagnosis of primary oropharyngeal malignancies particularly squamous cell carcinomas (SCC) and assessment of the spread. Fortunately, SCC of different regions of the oropharynx displays their distinctive pattern of spread. Knowledge of the anatomy and the common spread patterns have significant role in the assessment of primary SCC of the oropharynx and the staging process which in turn dictates the treatment plans. This exhibit discusses the anatomy of the oropharynx, imaging findings of mucosal primary and lymph nodal spread and how imaging can influence the TNM staging. The common pathways of tumour spread of oropharyngeal subsites are also elaborated. Anatomy: The squamous epithelium within the oropharynx is derived from endoderm and demonstrates greater potential for the development of poorly differentiated, aggressive carcinomas as compared to the oral cavity which is derived from ectoderm. Therefore, knowledge of the anatomical divisions will allow better prognostic prediction [1]. Anteriorly, the oropharynx is separated from the oral cavity by the junction between the hard palate and the soft palate, the oral tongue and the base of tongue, and the floor Page 2 of 40

3 of the mouth and the anterior tonsillar pillars. The superior and inferior margins of the oropharynx are delineated by the plane of the soft palate and the upper border of the epiglottis respectively. Posteriorly, the oropharynx is bounded by prevertebral facia and the bodies of the C2 and upper part of the C3 vertebrae. Within the boundaries of the oropharynx, the structures of note are the base (posterior one third) of the tongue, the palatine tonsils enclosed by the anterior and posterior tonsillar pillars, the soft palate and the posterior wall. (Fig. 2 on page 4, Fig. 3 on page 5, Fig. 4 on page 5, Fig. 5 on page 6, Fig. 6 on page 6, Fig. 7 on page 7) Epidemiology: Oral and pharyngeal cancers, when grouped together are the sixth most common cancer [2] in the world with a 5 year survival rate of 50% in most countries. In Australia, the incidence of oropharyngeal malignancies reported by Ariyawardana A and Johnson N showed an annual increase of 1.2% from 1982 to 2008 despite a decline in the overall rates of lip/oral/oropharyngeal cancer [3]. Squamous cell carcinoma (SCC) accounts for more than 90% of the malignant lesions in the oral cavity and the oropharynx with the most commonly recognised risk factors being [1] prolonged use of alcohol and tobacco smoking. Furthermore, Human Papilomavirus (HPV), (particularly HPV16, 90-95% of all HPV+ve oropharyngeal SCC) has been shown to be associated with SCC of the upper aerodigestive tract with increasing incidence from [4] 19% in to 47% in and 60% in Trials have demonstrated a better prognosis associated with HPV+ve SCC with an improvement in 2 year survival rate of both stage 3 and 4 SCCs as compared with HPVve SCCs (87.5% and 95% compared with 67.2% and 62%) should warrant the diagnosis of HPV status in patients. [5,6]. The better prognosis Images for this section: Page 3 of 40

4 Fig. 1: T1W Sagittal image demonstrating the division of the pharynx. Page 4 of 40

5 Fig. 2: CT Anatomy of Oropharynx Fig. 3: CT Anatomy of Oropharynx Page 5 of 40

6 Fig. 4: MR Anatomy of Oropharynx Fig. 5: MR Anatomy of Oropharynx Page 6 of 40

7 Fig. 6: MR Anatomy of Oropharynx Page 7 of 40

8 Fig. 7: Diagrammatic representation of the buccal region and the lateral wall of the oropharynx. Demonstrating the relative locations of the Retromolar trigone, the Anterior tonsillar pillar and the Palatine tonsil. Page 8 of 40

9 Methods and materials Imaging Modalities CT and MRI are the modalities of choice in assessing the morphology of the primary lesions and their association with adjacent structures. Nodal involvement can also be evaluated particularly with the use of MRI. PET imaging are also used frequently to depict nodal status and distant metastasis, therefore has a crucial role in treatment planning when used in conjunction with other modalities. SCC is the most common histopathological type of malignancy affecting the oropharynx and it can spread in three possible ways: 1. local extension of the tumour over mucosal surfaces, muscles and bones. 2. Spread via lymphatic drainage. 3. Invasion of the neurovascular bundle. Evaluation of these three spread patterns is essential for accurate staging. On CT with contrast, large tumours are easily identifiable and often display heterogeneity due to areas of necrosis. However, small mucosal primaries are not well characterised and extent of infiltration is difficult to identify especially in the presence of dental artefacts, rendering CT suboptimal in these settings. CT still retains its value in demonstrating bone involvement and erosion, they are displayed on bone windows as an interruption or an [8] erosion of the hyperattenuating rim. High resolution MR, 3.0T MRI scores over CT in depicting accurate localisation of primary, infiltration and spread across the midline. On T1 weighted MRI, most tumours appear hypointense whereas they appear hyperintense on T2 weighted images. With gadolinium contrast, solid tumours will enhance and necrotic appear hypointense. T1W images are useful in assessing the extent of the primary tumours and the spread as a result of natural contrast provided by the fat which has high signal additionally T1 W images also help in detecting neurovascular and bone marrow involvement. One drawback of MR imaging is the possible production of suboptimal images due to motion and breathing artefacts, tumour size can also sometimes be over-estimated in the [1] presence of haemorrhage and inflammatory changes. Higher spatial resolution offered by MRI is useful in assessment of the bone marrow involvement, neurovascular bundle encasement, prevertebral space involvement and perineural spread. Page 9 of 40

10 Results [1, 7] Primary Sites of Oropharyngeal Tumors 1) Base of Tongue (BOT) (Fig. 8 on page 15, Fig. 9 on page 16, Fig. 10 on page 17, Fig. 11 on page 18, Fig. 12 on page 19, Fig. 13 on page 20, Fig. 14 on page 21) Tumours of the BOT are insidious, often clinically occult and therefore present in advanced stages. Unilateral involvement of the BOT is common, crossing the midline only when the tumour becomes too large. MRI is the modality of choice in assessing the extent of the lesion. Axial images are superior in assessing the size, midline spread and the involvement of the soft palate and tonsillar region. Coronal images are useful in evaluating the floor of mouth, while the sagittal images provide information on the extent of pharyngeal infiltration. Involvement of deep intrinsic muscles of the tongue is best assessed on MRI 2) Tonsil (Fig. 15 on page 22, Fig. 16 on page 24, Fig. 17 on page 24, Fig. 18 on page 24, Fig. 19 on page 25) [9] The tonsillar region is the most common site of oropharyngeal SCC development. Tumours can originate from the tonsils, the tonsillar fossa, the anterior tonsillar pillars or the posterior tonsillar pillars with the anterior tonsillar pillars being the most common sites of primary lesions. Lesions are often exophytic or ulcerative in nature. SCC within the tonsillar fossa are mostly clinically occult and may present initially with cervical lymphadenopathy. Lesions often involve either the anterior or the posterior tonsillar pillar and therefore acquire the spread patterns of the lesions located in those regions. Isolated tumours of the posterior tonsillar pillars are rare and lesions are usually smaller than those found in other tonsillar regions. 3) Soft palate/uvula Page 10 of 40

11 (Fig. 20 on page 27, Fig. 21 on page 27) Tumours of the soft palate tend to be superficial and well differentiated. They are mostly diagnosed in the earlier stages and have better prognosis than other SCC of the oropharynx. The oral aspect of the soft palate is the most common location of SCC occurrence whereas the nasopharyngeal aspect is often speared even when the lesion is large. 4) Posterior pharyngeal wall (Fig. 22 on page 28) SCC originating from the posterior pharyngeal wall are rare and carry poor prognosis. Tumours commonly presents as exophytic mucosal masses extending to the nasopharynx or the hypopharynx. Miscellaneous malignant tumors SCC are the most common malignant tumors found in the oropharynx. Other rare malignant tumors include minor salivary gland carcinomas (Fig. 23 on page 30, Fig. 24 on page 30), lymphomas and lymphoepitheliomas. Minor salivary gland carcinomas have the highest frequency of occurrence in the posterior hard palate and the soft [7] palate. Non-Hodgkin's lymphoma presents as extranodal lymphatic disease due to the abundance of lymphoid tissues in the oral pharynx, they present as large, homogenous lesions on imaging studies. Lymphatic Spread SCC of the oropharynx predominantly drain into cervical lymph nodes level II, level III (American Joint Committee on Cancer (AJCC)) (Fig. 25 on page 31)and also the retropharyngeal nodes which are not covered by the standard nodal system. Level II nodes are located between the base of skull and the lower body of the hyoid bone; posterior to the back of the submandibular gland and anterior to the posterior border of the sternocleidomastoid (SCM) muscle. Level III nodes are between the lower body of the hyoid and the lower cricoid arch, lateral to the medial margin of the common carotid artery and anterior to the posterior border of the SCM. The retropharyngeal nodes which are within 2cm of skull base and medial to the internal carotid arteries are divided into the medial and lateral groups; the medial group is found in the suprahyoid retropharyngeal space, the lateral group is located between the carotid artery and the longus colli muscles. Page 11 of 40

12 Lymphatic involvement is the single most important prognostic factor. Of patients with oropharyngeal SCC, approximately 65% will have cervical lymphadenopathy. In particular, SCC of the BOT has the highest potential of lymph node involvement, followed by SCC of the tonsillar fossa. Bilateral nodal involvement is more prevalent with tumours of the posterior pharyngeal wall, soft palate and the base of tongue as extension beyond the midline is common. The cardinal features of malignancy are enlargement, heterogeneity and necrosis. With regards to the size criteria, malignancy is indicated if the maximum longitudinal diameter is greater than 15mm for jugulodigastric nodes (part of leveii), greater than 8mm for retropharyngeal nodes or greater than 10mm for any other nodes. However, if more than 3 nodes of greater than 8mm are found in the same lymphatic drainage area, nodal [1] metastasis is also likely. CT is the primary imaging modality in detecting nodal involvement of oropharyngeal SCC. Other than the size criterion, other crucial findings of malignancy include the loss of ovoid shape, heterogeneous enhancement with necrotic centres and extracapsular spread. HPV+ve SCC may also present with cystic adenopathy which may be mistaken for benign lesions. Contralateral or bilateral involvement of cervical nodes are often associated with large tumours crossing the midline and shows strong correlation with a [10, 11] worse prognosis, therefore requires more aggressive treatment. In the presence of streak artefacts from dental fillings or the involvement of the retropharyngeal nodes are suspects, MR imaging becomes the modality of choice. Extracapsular spread [1] increases the rate of local recurrence by 3.5times and is best demonstrated using MRI. Features of extracapsular spread include poorly defined nodal margins, irregular rimlike enhancement and increased soft tissue intensity surrounding the nodes. Neurovascular Invasion Invasion of local neurovascular structures are highly suggestive of distal metastasis. Perineural spread is rare in the setting of oropharyngeal SCC. Deep invasion of the carotid sheath leads to the encasement of the carotid artery which is best demonstrated on MRI. If encasement of vasculature is present, the tumour is deemed inoperable. TNM Staging Page 12 of 40

13 The TNM staging process based on the AJCC is best used to describe, oropharyngeal SCC whilst also assists in predicting the prognosis and constructing treatment plans. (Table 1 on page 32) [1, 8, 9, 12] Primary Tumors - Pathways of Spread Base of Tongue (Fig. 26 on page 33): Tumors usually spread along the palatoglossus muscle to involve the anterior tonsillar pillar; or spread anteriorly into the body of the tongue and the floor of the mouth. Tongue base tumor can cross the glosso-tonsillar sulcus and involve the tonsillar fossa Tumours may also invade inferiorly, affecting the vallecula and the pyriform sinus and into the pre-epiglottic space. Inferolateal spread into the deep soft tissues of the neck may eventually lead to the involvement of the styloid musculature and the internal carotid artery. Tonsils (Fig. 27 on page 34): Tumors of the anterior tonsillar pillars commonly invade the palatoglossus muscle superiorly to involve the lateral aspect of the soft palate. Tonsilllar primaries commonly cross the glosso-tonsillar sulcus and involve the tongue base Other sites of spread include retromolar trigone and the buccal mucosa. In advanced cases, lesions may involve the parapharyngeal space, the mandible and/or spread along the pharyngeal wall to the naso/hypo-pharynx. In advanced stages, spread to the skull base along the tensor and levator veli palatini muscles may be seen. Lesions found on the posterior tonsillar pillar tend to spread along the palatopharyngeus muscle superiorly to involve the soft palate, inferiorly to involve the thyroid cartilage, the middle pharyngeal constrictors and the pharyngoepiglottic fold. Soft Palate (Fig. 28 on page 35): Although tumours can extend in any direction, anterior spread is the most common and therefore the hard palate and the tonsillar regions are often the first structures to be affected. Deep invasion of the parapharyngeal space along the tensor veli palatini and levator veli palatini muscles laterally is rare and is seen in Page 13 of 40

14 advanced stages, where they may be associated with the involvement of the external carotid artery and skull base. Neural spread along the palatine branch of the maxillary nerve, the greater and lesser palatine nerves to the skull base can occur which may lead to the involvement of the cavernous sinus. Posterior Pharyngeal Wall (Fig. 29 on page 35): SCC of the posterior pharyngeal wall are commonly found to spread into the retropharyngeal space and infiltrate the prevertebral fascia. Involvement of the prevertebral space and the paravertebral muscles precludes surgery. Lesions can also spread superiorly into the nasopharynx or inferiorly to involve the pyriform sinus and the hypopharyngeal wall. Most lesions cross the midline and therefore bilateral cervical lymph node involvement is common. Difference between HPV+ and HPV- SCC of the oropharynx HPV+ve SCCs (Fig. 30 on page 35)tends to present with smaller, exophytic lesions with well-defined borders, they are associated with bulky cervical nodal involvement of cystic appearance on CT. HPV+ve SCCs are more likely to arise from the BOT and the tonsils than their HPV-ve counterparts [13]. On imaging, HPV-ve SCCs (Fig. 31 on page 36) display ill-defined borders, invasion of adjacent muscles is also common. Compared to HPV+ve SCCs of the oropharynx, HPV[5, ve SCCs are diagnosed at later stages and are also associated with a worse prognosis 6]. Discussion and Management Although head and neck cancers display a decreasing trend globally, the incidence of oropharyngeal cancers is rising. This is particularly due to the clinically occult nature of oropharyngeal tumours and the increase in the incidence of HPV positive oropharyngeal SCC. Currently, the diagnosis and staging relies on using imaging studies, predominantly CT scans and MR Imaging. As SCC of each subsite displays their unique spread patterns, Page 14 of 40

15 information regarding the tumour and the extent of spread can be assess with great accuracy using the aforementioned modalities. The management of oropharyngeal SCC depends on the stages of the presenting tumours. Smaller lesions (T1 or T2) are usually treated with single modality therapy (either radiotherapy (Fig. 32 on page 37, Fig. 33 on page 38) or surgery). However structures such as the soft palate or the uvula have significant role in palatal function [8] therefore are often managed with radiotherapy. Large tumours may be treated surgically with adjuvant radiotherapy. In the case of inoperable tumours and those with relative contraindications to surgery such as bilateral involvement of the base of tongue, extension of the tumour to the larynx, combined [8] chemotherapy and radiotherapy is the treatment of choice. In the presence of nodal involvement, neck dissection is usually indicated with curative intent. Due to the predictable pattern of spread of oropharyngeal SCC, selective dissection of the lateral neck (levels II - IV) will most often suffice. The area of which is marked by the medial border of the sternothyroid and the posterior border of the sternocleidomastoid, extending from the skull base to the clavicle. The spinal accessory nerve, internal jugular vein and the sternocleidomastoid muscle are spared in this procedure. In the presence of extensive nodal disease, i.e. presence of N3 nodes, clinically evident nodes, involvement of neurovascular or musculoskeletal structures, extranodal spread or recurrence of nodal disease, a radical neck dissection is indicated. Radical neck dissection involves the removal of all ipsilateral nodes from level I through to V and also the spinal accessory nerve, the internal jugular vein and the sternoceidomastoid muscle. A modified radical dissection can also be performed when one or more of the aforementioned non-lymphatic structures can be preserved. The name(s) of which should be included in the procedural detail. In case of more advanced disease, the radical neck dissection may need to include structures outside the scope described above in order to achieve negative margins. The procedure therefore will be termed extended neck dissection and the procedural details should include the structures resected e.g. the retropharyngeal nodes, the hypoglossal nerve or the prevertebral musculature. Images for this section: Page 15 of 40

16 Fig. 8: Exophytic right tongue base mass extending across the midline with necrotic right level 2 lymphadenopathy Page 16 of 40

17 Fig. 9: Endoscopy recording demonstrating right sided BOT mass. Same patient as shown in Fig. 8 Page 17 of 40

18 Fig. 10: Infiltrative mass predominantly centred in the left tongue base with extension to the left tonsillar fossa, retromolar trigone. Post-contrast image demonstrates uniform enhancement of the mass. Page 18 of 40

19 Fig. 11: Large infiltrating mass of base of tongue with invasion of the intrinsic muscles of the tongue. Tumor involves the entire tongue base with effacement of the valleculae and epiglottis. Page 19 of 40

20 Fig. 12: Small ulcerated right tongue base primary with deep intrinsic muscle invasion. Extension to right lateral wall of oropharynx is seen. Note necrotic right level II/III lymphadenopathy with frank extracapsular spread and extensive infiltration. Page 20 of 40

21 Fig. 13: PET CT avid small right tongue base primary with extensive nodal disease in right neck. Page 21 of 40

22 Fig. 14: Right BOT mass with involvement of the entire tongue base and intrinsic muscle of the tongue. The lesion extends beyond the lingual septum to involve the left tongue base as well. Note the involvement of the oral tongue. Page 22 of 40

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24 Fig. 15: Necrotic enhancing mass lesion involving the right tongue base extending into the right lateral wall of the oropharynx, tonsillar fossa with minimal extension to the right retromolar trigone. FDG avid primary lesion with an SUVmax of approximately 11.9 in the right glossotonsillar sulcus. Fig. 16: Enhancing right tonsillar primary causing effacement of glosso-tonsillar sulcus with no tongue base invasion. Fig. 17: Same patient as Fig 15 demonstrating FDG avid right tonsillar primary. Page 24 of 40

25 Fig. 18: Right tonsil primary seen crossing the glossotonsillar sulcus to involve the right BOT. Also seen is infiltration to the right retromolar trigone.note extensive right level II/III necrotic lymphadenopathy with extracapsular spread and extension to the neurovascular bundle. Page 25 of 40

26 Fig. 19: Infiltrative and invasive mass lesion of the right tonsil is identified. There is effacement of the right glossotonsillar sulcus with localised invasion of the right tongue base. Note spread of the primary tumour laterally beyond the margins of the oropharynx causing dehiscence of the right mylohyoid sling and extending into the right submandibular space. Page 26 of 40

27 Fig. 20: Exophytic mass is seen arising within the uvula, left lateral wall of the oropharynx. The mass extends along the left lateral wall of the oropharynx medially causing a bulky appearance of the uvula which is well demonstrated on T1W and T2W fat sat sagittal image. Page 27 of 40

28 Fig. 21: T2 fat Sat Images show heterogeneous mass involving the soft palate. Tumour extends laterally to involve the right retromolar trigone, reaching the junction of the right ramus of the mandible and posterior margin of the maxillary dental arch without infiltration into the right buccal sulcus.the tumour extends posteriorly to the right tonsillar bed and medial extension is seen up to the midline. There is no definite evidence of uvula involvement. Page 28 of 40

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30 Fig. 22: Irregular right posterior pharyngeal wall mass with extension to the tonsillar fossa. Note the tumor crossing midline, prevertebral space extension is likely. Fig. 23: Circumferential tongue base mass effacing the valleculae.mass appears hyperintense on T2 W FS images with heterogeneous enhancement.imaging appearance not typical of SCC. Histopathology confirmed a minor salivary gland tumor. Page 30 of 40

31 Fig. 24: Right tongue base mass in a 20 y old female.mass has well defined margins and appears slow growing.t2 W images have a high signal and mass enhances with contrast.histopathology confirmed Mucoepidermoid carcinoma. Page 31 of 40

32 Fig. 25: Diagrammatic representation of the neck showing various nodal levels Page 32 of 40

33 Table 1: Tumor, Node, Metastasis (TNM) staging for oropharyngeal cancer Page 33 of 40

34 Fig. 26: Spread patterns of tongue base primary Fig. 27: Spread patterns of tonsillar primary. Page 34 of 40

35 Fig. 28: Spread patterns of soft palate primary. Fig. 29: Spread patterns of posterior pharyngeal wall primary. Page 35 of 40

36 Fig. 30: Contrast enhanced CT demonstrates a typical HPV +ve tonsillar primary with large cystic nodes in right level II/III Page 36 of 40

37 Fig. 31: Two different HPV -ve tumors with tongue base (a-1,a-2) and tonsillar(b-1,b-2)primaries.note large fleshy primaries with solid nodes with necrosis and extracapsular spread. Page 37 of 40

38 Fig. 32: Contrast enhanced CT demonstrates diffuse mucosal edema involving the oropharynx as a result of recent radiotherapy. Fig. 33: T2 Fat sat images show marked high signal within the left nasopharynx and lateral wall of the oropharynx suggestive of oedema in keeping with post-radiotherapy changes. Scar tissue is identified within the left tonsillar bed also as a result of previous radiation.mucosal enhancement is seen on post contrast images. Page 38 of 40

39 Conclusion Oropharyngeal cancers are on the rise and understanding the anatomy and the patterns of tumor spread is valuable and imaging forms an integral component of multi-disciplinary mangement of the tumors. As SCC of the oropharynx displays unique characteristic on CT and MRI, multimodalty imaging provides accurate information on local spread, neurovascular invasion and most importantly nodal involvement which in turn influences patients' TNM staging and treatment plan. Personal information Corresponding Author Dr.Sandeep Bhuta MBBS,DMRD,DNB,FRANZCR Associate Professor & Neuroradiologist Dept.of Medical Imaging,1 Hospital Boulevard, Griffith University,School of Medicine Gold Coast University Hospital, Gold Coast, QLD,4215 Australia References Trotta BM, Pease CS, Rasamny JJ, Raghavan P, Mukherjee S (2011) Oral cavity and oropharyngeal squamous cell cancer: key imaging findings for staging and treatment planning. Radiographics 31: doi: / rg Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncology. 2009; 45: Ariyawardana A, Johnson NW. Trends of lip, oral cavity and oropharyngeal cancers in Australia : overall good news but with rising rates in the oropharynx. BMC Cancer. 2013;14:333. Page 39 of 40

40 Hong AM, Grulich AE, Jones D, Lee CS, Garland SM, Dobbins TA, et al. Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine2010;28: Epub 2010 Mar. Worden FP, Kumar B, Lee JS, Wolf GT, Cordell KG, Taylor JM, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol2008;26: Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst2008;100: Tibrewala S, Roplekar S, Varma R. Computed Tomography Evaluation of Oral Cavity and Oropharyngeal Cancers. Int J Otorhinolaryngol Clin 2013; 5(2): Tshering Vogel DW, Zbaeren P, Thoeny HC. Cancer of the oral cavity and oropharynx. Cancer Imaging. 2010;16: Choi WH, Hu KS, Culliney B, et al.: Cancer of the oropharynx. In: Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Philadelphia, PA: Lippincott, William & Wilkins, 2009, pp Lim YC, Koo BS, et al. Distributions of cervical lymph node metastases in oropharyngeal carcinoma: therapeutic implications for N0 neck. Laryngoscope2006;116 (7) Capote-Moreno A, Naval L, Muñoz-Guerra MF, et al. Prognostic factors influencing contralateral neck lymph node metastases in oral and oropharyngeal carcinoma. J Oral Maxillofac Surg 2010; 68: Mukherji S, Armao D, Joshi V. Cervical nodal metastases in squamous cell carcinoma of the head and neck: What to expect. Head and Neck 2001; 23: Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM, Ginsberg LE. Differences in imaging characteristics of HPV-positive and HPV-negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR Am J Neuroradiol [Epub 2013/05/11] doi: [pii] /ajnr.A3524. Page 40 of 40